1. Field of the Invention
The present invention relates to liposome incorporated anthracycline derivatives and their use in pharmaceutical compositions for the treatment of cancer.
2. Description of the Related Art
Anthracyclines are a group of antibiotics which have shown significant antitumor activity against several types of human tumors. The most widely used anthracycline, doxorubicin (adriamycin) is a natural product produced by bacteria. Doxorubicin is used as front line therapy against human leukemia, lymphoma, and disseminated human solid tumors (breast, lung, GI, ovary, testicle, etc.). Unfortunately, the use of doxorubicin is severely limited by acute and chronic side effects. Acute side effects such as myelotoxicity limit the amount of doxorubicin that can be administered at one time to a patient. Chronic side effects such as cardiotoxicity limit the use of doxorubicin beyond a cumulative dose of 550 mg/m sq.
During the last decade, a number of anthracyclines have been synthesized in an attempt to decrease the above mentioned side effects. However, none of the analogues that were selected for further development was shown to be clearly superior to doxorubicin in the clinic. Very promising analogues were, however, never selected for preclinical development and fully evaluated in part due to formulation problems in aqueous solutions.
an alternative approach that has been attempted in an effort to improve the pharmacological properties of anthracycline antibiotics is the use of drug carrier techniques such as liposome incorporation. Liposomes are lipid vesicles that form spontaneously upon addition of aqueous solutions to a dry lipid film. Liposomes may entrap drugs in their hydrophilic or lipophilic compartments. Liposomes target mainly to the organs rich in reticuloendothelial system cells although they may also deliver drugs to different types of tumors, specially tumors that involve or arise in these organs.
Liposomes have been employed as carriers of doxorubicin. Incorporation of doxorubicin in liposomes was found generally to result in lower cardiac drug levels, and in a significantly deceased cardiotoxic potential. Unfortunately, all liposomal-anthracycline preparations developed so far have exhibited a low encapsulation efficiency and a poor stability because doxorubicin tends to leak out of the vesicles. Moreover, encapsulation and stability is generally not improved by changing the composition of the liposomes used. These negative characteristics have prevented the wide use of liposomal-doxorubicin in the clinic as a way to decrease the cardiotoxicity of the drug and increase its efficacy against certain types of tumors which are a natural target for liposomes, for example, tumors of monocyte/macrophage lineage and liver metastases of gastrointestinal malignancies.
Due to the importance of anthracycline therapy in the treatment of cancer, there is a continuing need to identify anthracycline derivatives that may be stably incorporated into liposomes in a high enough efficiency to provide novel compositions useful in the treatment of cancer. Additionally, there is a need to provide anthracycline containing compositions having improved antitumor characteristics, including an improved antitumor spectrum, bioavailability and distribution, as well as an improved cardiotoxicity. Unfortunately, these needs have generally gone unfulfilled.